I. The Complement System
The complement system is a complex interaction of at least 25 plasma proteins and membrane cofactors which act in a multistep, multiprotein cascade sequence in conjunction with other immunological systems of the body to defend against intrusion of foreign cells and viruses. Complement proteins represent up to about 10% of globulins in normal serum of humans and other vertebrates. Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonic, immunoregulatory, and lytic functions.
There are two main routes of complement activation: the classical pathway and the alternative pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same "terminal complement" components responsible for the activation, attack, and/or destruction of target cells.
The classical complement pathway is typically initiated by antibody recognition of and binding to an antigenic site on a target cell. The alternative pathway is usually antibody independent, and can be initiated by certain molecules on pathogen surfaces. Both pathways converge at the point where complement component C3 is cleaved by an active protease (which is different in each pathway) to yield C3a and C3b. The active protease, which is referred to as C3 convertase, comprises complement components C2aC4b for the classical pathway and complement components C3bBb for the alternative pathway.
C3a is an anaphylotoxin that can induce degranulation of mast cells, resulting in the release of histamine and other mediators of inflammation. C3b has multiple functions. As opsonin, it binds to bacteria, viruses and other cells and particles and tags them for removal from the circulation. C3b can also form a complex with other components unique to each pathway to form classical or alternative C5 convertase, which cleaves C5 into C5a (another anaphylatoxin), and C5b.
C5a, like C3a, is a potent anaphylatoxin which can cause the activation of granulocytes and platelets. Additionally, C5a is a chemoattractant for neutrophils and also mediates mast cell histamine release and resulting smooth muscle contraction. C5b, on the other hand, combines with C6, C7, and C8 to form the C5b-8 complex at the surface of the target cell. Upon binding of C9 the membrane attack complex (MAC, C5b-9) is formed. When sufficient numbers of MACs insert into target cell membranes, the openings they create mediate rapid lysis of the target cells. Lower, non-lyric concentrations of MACs can produce other effects. In particular, membrane insertion of small numbers of the C5b-9 complexes into endothelial cells and platelets can cause potentially deleterious cell activation. In some cases activation may precede cell lysis.
Control of the complement system is necessary in order to prevent destruction of autologous cells. Since 1900 it has been known that complement-mediated cytolysis is not efficient when the complement and the target cells are from the same species. (Border, 1900.) Studies on the susceptibility of non-human cells to complement-mediated lysis have shown that such cells are readily lysed by human complement while they are generally resistant to lysis by complement derived from the same species. (Houle et al., 1988). This phenomenon is referred to in the art as "homologous species restriction of complement-mediated lysis." The mechanism by which such restriction takes place has been at least partially revealed by a series of experiments in which complement regulatory proteins have been identified that serve to protect cells from homologous complement-mediated damage. (Rollins et al., 1991).